Process for the preparation of compounds having ACE inhibitory action and intermediates in said process

ABSTRACT

There is disclosed a process for the preparation of compounds having ACE inhibitory action of the formula ##STR1## wherein R has the meanings as in claim 1, wherein the stereospecific amino acid N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine is carboxylically activated with a thionyl chloride derivative wherein at least one chlorine atom is replaced by the residue of a heterocyclic ambident compound such as imidazole, benzimidazole, 2-methylimidazole or triazole, especially chlorothionylimidazole or thionyldiimidazole, in the presence of an organic solvent to the intermediate novel compound A or to the intermediate novel compound B and the obtained intermediate compound is reacted with an amino acid, preferably in the monosilylated form, most preferably in the disilylated form. Disclosed are also novel compounds useful as starting materials or intermediates in the present process.

This application is a 37-1 of PCT/SI95/00017 Jul. 13, 1995.

This application is a 37-1 of PCT/SI95/00017 Jul. 13, 1995.

TECHNICAL FIELD

The present invention belongs to the field of the organic chemistrysynthesis and refers to a process for the preparation of compoundshaving ACE inhibitory action as well as to novel compounds useful asstarting materials or intermediates in the said process.

TECHNICAL PROBLEM

There was a need for a simple and industrially convenient process forthe preparation of compounds having ACE inhibitory action.

PRIOR ART

In EP 0215335 there is disclosed a process for activating N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine with phosgene or polymersthereof to N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanineN-carboxyanhydride. The reaction yields are very high but the processnecessitates the use of a highly toxic reagent for the preparation of anactive intermediate. During the reaction phosgene polymers decompose tophosgene, which leaves the reaction medium. A fresh reagent must beadded repeatedly. For carrying out the process, special industrialplants are necessary in order to prevent the contamination ofenvironment.

N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine N-carboxyanhydridereacts with organic and inorganic salts of L-proline. Reactions takeplace in a basic medium as to prevent possible reactions with thesecondary amino group.

It is well-known from the literature that for the formation ofN-carboxyanhydrides of amino acids also carbonyl diimidazole may be usedas a synthon for the formation of phosgene. The yields of acylationreaction depend upon the organic solvents used and water in the reactionsolution. In methanol the reaction yield is 41.4%, in dioxane 96% and inacetone 94%. The reaction results are determined by HPLC analysis.

In the said patent in the activation reaction of the starting N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine neither the racemizationon α-C atom of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanineN-carboxyanhydride is specified nor possible side reactions (J. Org.Chem., 32, 11, 1967) are mentioned. In the optimum Example 4 thereaction yield up to enalapril (base) is 87%. The separation ofenalapril maleate is carried out with a 81.8% yield.

In U.S. Pat. No. 4,374,829 a process for the preparation of enalaprilmaleate by asymmetric reduction of the corresponding starting Schiff'sbase is disclosed. In different reaction conditions, however, alwaysonly a mixture of stereospecific isomers is isolated.

In ES patent 2,004,804 the preparation of carboxyalkyldipeptides usefulas ACE inhibitors is disclosed. N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine is treated with1,1-carbonyldiimidazole in EtOAc and subsequently with L-proline andenalapril maleate is obtained with a 77% yield.

The Technical Solution

The first object of the invention is a process for the preparation ofcompounds having ACE inhibitory action of the formula ##STR2## andpharmaceutically acceptable salts thereof, wherein R has the followingmeanings ##STR3## characterized in that the carboxy group of thestereospecific amino acid N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine of the formula ##STR4##is activated with thionyl chloride derivative of the formula I' ##STR5##or with thionyl chloride derivative of the formula II' ##STR6## whereinR₁ is the residue of a heterocyclic ambident compound such as imidazole,benzimidazole, 2-methylimidazole or triazole, in the presence of anaprotic organic solvent under elimination of the precipitatedhydrochloride of the above mentioned heterocyclic ambident compound, tothe intermediate novel compound A ##STR7## or to the intermediate novelcompound B ##STR8## and the obtained intermediate compound (A, B) isreacted with an amino acid, preferably in its monosilylated form, mostpreferably in a disilylated form, selected from the group consisting of##STR9## whereat the reaction medium must be anhydrous in all steps, andthen the obtained compounds are converted to pharmaceutically acceptablesalts thereof in a conventional manner.

The starting stereospecific amino acid N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine is a well-known andcommercially available compound and is disclosed in EP 353350 A1 and inSpanish Patent Application 9400994.

As the thionyl chloride derivative of the formula I' useful as theactivating reagent e.g. chlorothionylimidazole of the formula (I)##STR10## may be used and as the thionyl chloride derivative of theformula II' useful as the activating reagent e.g. thionyldiimidazole ofthe formula (II) ##STR11## may be used.

The course of the activation of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine as the first process stepof the inventive process using the reagent (I) is illustrated byScheme 1. ##STR12##

The obtained imidazole hydrochloride (ImHCl) must be eliminated severaltimes since it coordinates either the starting stereospecific amino acidor the obtained novel intermediate A, B, thereby reducing the yield.

The organic solvents for the reaction are methylene chloride,dichloroethane, chloroform, toluene, benzene, heptane, hexane, whereasfor the extraction and isolation of the final product the solvents areethyl acetate, isopropyl acetate, t-butyl methyl ether. The reactionstake place at temperatures from -20° C. to room temperature.

Chlorothionylimidazole of the formula (I) is a known compound. The IRspectrum thereof is shown in FIG. 1.

Thionyldiimidazole of the formula (II), m.p. 78°-79° C., was firstsynthesized by Staab in 1961 (Angew. Chem. 76, 26, 1961) and has neverbeen used for the present purpose.

The remaining thionyl chloride derivatives useful as activating reagentsare available compounds.

Activating reagents are convenient for the activation of amino acids andorganic acids in general. Economically as well as ecologically, the saidreagents are advantageous over phosgene and polymers thereof as well asover carbonyldiimidazole (CDI).

The compound of the formula (I) or the compound of the formula (II) areprepared by a reaction of thionyl cloride (SOCl₂) and imidazole instoichiometric amounts and at temperatures in the range from -20° C. to+25° C.

The process for the preparation of the compound of the formula (I) iscarried out in such a way that thionyl chloride is reacted with astoichiometric molar amount of imidazole in an organic solvent underelimination of the formed imidazole hydrochloride (ImHCl).

Certain pharmaceutically acceptable salts of the compounds having ACEinhibitory action, of the above formula such as hydrochloride, sulfateand sodium salt are also novel and represent objects of invention.

As organic solvents the same solvents are used as in the process ofactivation of a stereospecific amino acid N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine.

The preparation of the compounds of the formulas (I) or (II) is shown inthe Scheme 2. ##STR13##

The test results show that the reaction yield of the obtained productdepends upon the imidazole concentration in the reaction medium.

In the course of the reaction the filtration of imidazole hydrochlorideis carried out twice. Im.HCl is sucked off for the first time in thepreparation of reagents (I) and (II) and for the second time after thereaction of activation of the amino acid N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine.

It is proceeded similarly in the preparation of the remaining activatingreagents.

The process yield or the yield of the final product may be improved insuch a way that the mixture of monosilylated and disilylated aminoacids, preferably in the ratio 1:1, is used for the reaction with aminoacid.

Namely, the effect of the reaction time on the formation of enalaprilwas observed. It was found that when starting from 1.4 g of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine and using L-proline asthe amino acid, the yield of the isolated enalapril in the doubledreaction time was reduced from 1.85 g to 0.5 g. It was surprisinglyfound that this loss may be practically avoided if in the reaction ofthe intermediate compound a mixture with only a part of disilylatedL-proline was used. The best results were obtained when a solution ofsilylated L-proline containing 50% of disilylated L-proline, i.e.L-proline-N-trimethylsilyl-O-trimethylsilyl ester of the formula##STR14## and 50% of monosilylated L-proline, i.e.L-proline-O-trimethylsilylester hydrochloride of the formula ##STR15##entered into the reaction and the reaction time was between 6 and 20hours.

Thus a mixture of L-prolin-N-trimethylsilyl-O-trimethylsilyl ester andL-prolin-O-trimethylsilylester hydrochloride in a 1:1 ratio was usedespecially preferably as the amino acid.

The intermediate compounds A and B are novel. The structure of the novelcompound A, whose IR spectrum is shown in FIGS. 3 and 3a, is confirmedby the following findings:

1) On the basis of the IR spectrum (FIG. 3) and by comparison thereofwith the IR spectrum of the N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acid chloride (FIG. 5) ofthe formula ##STR16## m.p. 119°-123° C., of the further reaction of thereagent (I) with N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine andof the IR spectrum of imidazole hydrochloride (FIG. 2), the structure ofthe compound A may be inferred;

2) The novel compound A does not react with imidazole

The reactivity of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acidchloride was tested and it was found that the reaction with imidazolewas spontaneous and the imidazole hydrochloride was separated thereat.It is well-known from the literature that by such reactivity a furtherconversion to the corresponding aldehydes and ketones is made possible(Liebigs Ann. 655, 90, 1969; Angew. Chem. Int. Ed. 1, 351 1962; Rec.Trav. 84, 213, 1965).

3) The IR spectrum of the solid form of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acid chloride (FIG. 5)shows oscillations at 1762 cm⁻¹ corresponding to the carbonyl group ofthe acid chloride, and oscillations at 1745 cm⁻¹ belonging to estergroup.

4) The IR spectrum of the novel compound A (FIG. 3) does not show asignal at 1762 cm⁻¹ but only at 1745 cm⁻¹.

5) The IR spectrum of the novel compound A (FIG. 3) in the finger printarea does not show that a mixture of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acid chloride andimidazole could exist. The IR of the novel compound A (FIG. 3) has avery similar spectrum as the one of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L alanine imidazolide (B) (FIG. 4).

6) In the IR spectrum of the novel compound A (FIG. 3), an absorptionband at 1625 cm⁻¹ can be noticed and in the spectrum of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acid chloride, anoscillation at 1585 cm⁻¹ can be noticed (FIG. 5), which corresponds to>N⁺ H₂ and looks like an intramolecular hydrogen bond activated with thecarbonyl group. The suggested structure blocks the amino group in N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine acid chloride.

7) In the IR spectrum of imidazolide (FIG. 4), the absorption(conjugated --C═N-- bond) at 1670 cm⁻¹ can be noticed; whereas in the IRspectrum of imidazole hydrochloride (FIG. 2) a vibration at 1580 cm⁻¹can be noticed.

8) The reaction of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanineacid chloride with disilylated L-proline takes place in the presence oftriethylamine at 20°-25° C. in about 5 minutes to give enalapril maleatewith a yield under 40%. The novel compound A (FIG. 3), however, reactswith disilylated L-proline under the same conditions essentially slower(more than 8 hours) with a yield over 80%. Also N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine imidazolide (B) in thepresence of imidazole hydrochloride and disilylated L-proline in 11hours gives only the product with a 41% yield.

9) If to the novel compound A (IR spectrum in FIG. 3) dimethylacetamidesulfate (VI) was added, which sulfate blocks a secondary amino group,only 50% of enalapril maleate were isolated. The said reaction shows aspecial importance of the intramolecular hydrogen bond between the NHgroup and the carbonyl group.

10) In the presence of humidity or water, protic solvents or at elevatedtemperature, the compound A is converted to a novel compound C, which,however, reacts neiher with monosilylated and disilylated amino acidsnor with salts of amino acids to the desired end products. ##STR17## 11)The compound C has a m.p. 109°-110° C. and is structurally a cyclicamide of the starting amino acid N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine. It is formedquantitatively from intermediate A.

12) 1,4-di(1-ethoxycarbonyl-3-phenyl)propyl-1!-3,6-dimethylpiperazine-2,5-dione(C) was characterized by NMR, IR (FIG. 10) and UV (FIG. 11) spectra, byelemental and mass analyses:

1. ¹ H--NMR (CDCl₃ ; TMS) 300 MHz: δ: 1.22 (t, 6H, --CH₂ --CH₃ ), 1.55(d, 6H, --CH--CH₃ ), 2.21-2.38 (m, 2H, Ph--CH₂ --CH₂ --CH), 2.42-2.58(m, 2H, Ph--CH₂ --CH₂ --CH), 2.73 (m, 4H, Ph--CH₂ --CH₂ --CH), 3.76 (t,1H, Ph--CH₂ --CH₂ --CH), 3.77 (t, 1H, Ph--CH₂ --CH₂ --CH), 3.86 (q, 2H,CH₃ --CH), 4.12 (q, 2H, --CH₂ --CH₃), 4.17 (q, 2H, --CH₂ --CH₃),7.10-7.25 (m, 10H, Ph).

2. ¹³ C (CDCl₃, TMS) 300 MHz: δ: 14.24 (CH₂ --CH₃), 19.59 (CH₃ --CH),30.81 (--CH₂ --CH₂ --Ph), 32.82 (--CH₂ --CH₂ --Ph), 58.93 (--CH--CH₃),59.94 (CH--CH₂), 61.73 (CH₂ --CH₃), 126.57, 128.61, 128.68, 128.75,128.89 (Ph), 167.26 (CO--N═), 169.96 (COOEt).

Elemental analysis for C₃₀ H₃₈ N₂ O₆ :

    ______________________________________                                        calc.:  68.94% C      7.33% H  5.36% N                                        found:  68.70% C      7.18% H  5.56% N                                        ______________________________________                                    

Mass spectrum (T=150° C.) m/e: 522 (M⁺, 87%), 477 (M⁺ --OEt, 17%), 449(M⁺ --COOEt, 8%), 418 (M⁺ --Ph--CH₂ --CH₂, 83%), 372 (M⁺ --Ph--CH₂ --CH₂--CH, 46%). m.p. 109°-110° C., M=522.12.

13) The reactions of forming activation reagents, activation of N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine with activation reagentsand reactions of disilylated amino acids with reagents A and B must becarried out in anhydrous aprotic solvents and at reduced temperature.Thus the formation of 1,4-di(1-ethoxycarbonyl-3-phenyl)propyl-1!-3,6-dimethylpiperazine-2,5-dione(C) is avoided.

14) The reaction yield primarily depends upon the formation of thecompound C. The formation of the compound C reduces the reaction yield.

It follows from the above data that in the reaction between thionylchloride and

a) imidazole (from 1.1743 to 1.3486 g) via the formation of the reagent(I) and the subsequent reaction of the reagent (I) with N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine a novel compound isisolated. On the basis of the experimental data and IR spectrum and onthe basis of the comparison of the latter with the spectra of relatedcompounds, there was suggested the structure A for the novel compoundhaving the corresponding IR spectrum (FIG. 3), NMR spectrum and UVspectrum (FIG. 12) ##STR18## ¹ H--NMR (CH₂ --CH₂, TMS) reaction mixture:δ: 1.15 (t, 6H, --CH₂ --CH₃ ), 1.40 (d, 6H, --CH--CH₃ ), 1.80-2.10 (m,2H, Ph--CH₂ --CH₂ --CH), 2.50-2.80 (m, 2H, Ph--CH₂ --CH₂ --CH), 3.22 (t,2H, Ph--CH₂ --CH₂ --CH), 3.95 (q, 2H, --CH--CH₃), 4.12 (q, 4H, --CH₂--CH₃), 7.10-7.45 (m, 10H, Ph), 7.65 (d, 1H, H_(4')), 7.70 (d, 1H,H_(5')), 8.45 (m, 1H, H_(2')). FAB⁺ (m/e): 591 (M⁺ --HCl, 9%), 523(10%), 234 (82%), 160 (15%), 150 (25%), 137 (42%), 117 (25%), 91 (57%),69 (100%).

b) imidazole (2.4770 g) via reagent (II) and the subsequent reaction ofthe reagent with N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine anovel compound having the structure B and IR spectrum (FIG. 4) isisolated. ##STR19##

The structure of the novel intermediate compounds A or B and the systemalone of running the reaction made possible the selectivity of thereaction, the absence of racemization and a high yield (at the compoundA) of the reaction for preparing compounds having ACE inhibitory actionaccording to the invention when compared to EP 0215335. The processalone is simple and industrially promising.

the invention is illustrated by the following Examples.

EXAMPLE 1

A) Process for the preparation of enalapril maleate

Preparation of reagent I

A solution (50 ml) of SOCl₂ (1 ml) in methylene chloride was prepared.The solution (22 ml) was portioned out and another 3 ml of driedmethylene chloride (SOCl₂ : 0.44 ml, 6.064 mmole) were added. Thereaction mixture was cooled to -20° C. and to the reaction mixture acorresponding amount of imidazole (Table 3) was added. A slightlyexothermic reaction was observed and the temperature rose to -15° C. Thereaction was led according to Table 1. The solid precipitate wasfiltered off and washed with methylene chloride (5 ml). Imidazolehydrochloride was dried.

                  TABLE 1                                                         ______________________________________                                        reaction time temperature                                                     (min)         (°C.)                                                                            remarks                                               ______________________________________                                         0            -15       white precipitate                                     12            -10       white precipitate                                     23             -4       white precipitate                                     40             +4       white precipitate                                     55            +17       white precipitate                                     65            +25       white precipitate                                     ______________________________________                                    

Activation of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine

N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine (1.4 g) was added tothe solution of reagent (I), stirred for 45 minutes at a temperaturefrom -15° C. to 0° C. and then for 15 minutes at a temperature from 0°C. to +15° C. and finally for 5 minutes at a temperature from +15° C. to20° C. (Table 2).

                  TABLE 2                                                         ______________________________________                                        reaction time  temperature                                                    (min)          (°C.)                                                                            remarks                                              ______________________________________                                         0             -15       suspension                                           10             -10                                                            25              -5                                                            35              -5                                                            45              +1                                                            50              +6                                                            60             +12                                                            65             +20                                                            ______________________________________                                    

After the completed reaction, the second filtration (amounts see Table3) was carried out and the solids were washed with dry methylenechloride (5 ml).

Disilylation of L-proline

While preparing the intermediate A, a silylation of L-proline tookplace. A mixture of anhydrous methylene chloride (25 ml) and L-proline(0.69 g; not soluble in the solvent) and triethylamine (1.7 ml) wastaken. Trimethylsilyl chloride (1.6 ml) was added to the reactionmixture. A slightly exothermic reaction was observed. Insolubletriethylammonium hydrochloride precipitated from the reaction mixture.The reaction mixture was stirred at room temperature for 150 minutes.

Acylation of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine

The reaction mixture of disilylated L-proline was added to the solutionof the activated N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine andthe reaction mixture was stirred at room temperature (Table 3). Thecolour of the solution was from pale yellow to a darker colour.

Isolation

The solvent was evaporated on rotavapor. Water (10 ml) saturated withNaCl (3 g) was added. Ethyl acetate (5 ml) was added. The pH wasadjusted from 6 to 4.2 with a 35% HCl solution. The yellowish organicphase was decanted and the aqueous phase was extracted with ethylacetate (3×3 ml). The combined organic phases were dried over anhydroussodium sulfate. If necessary, activated carbon was added to thesolution. The solution was filtered off, washed with ethyl acetate (3×3ml) and fresh solvent (4 ml) was added. Maleic acid (0.6 g) was addedcontinuously. Enalapril maleate began to precipitate at once. Thereaction mixture was stirred for 15 minutes at 25° C., cooled to -20° C.and stirred for another 20 minutes. The reaction mixture was left towarm to -15° C., filtered, washed with ethyl acetate (3 ml) and dried(Table 3).

                  TABLE 3                                                         ______________________________________                                                 imidazole           time of                                                   hydrochloride       acyla-                                           imidazole                                                                              (g) filtration                                                                           L-proline                                                                              tion  enalapril maleate                          (g)      1.     2.      (g)    (h)   m (g)                                                                              yield (%)                           ______________________________________                                        a.  1        1.26   --    0.69   18    1.7  69.1                              b.  1        0.82   0.45  0.69   24    1.8  73.2                              c.  1.1743   1.26   --    0.69   18    1.77 72                                d.  1.1743   1.06   0.25  0.8     2    1.25 50.8                              e.  1.3486   1.18   0.03  0.69    2    1.67 67.8                              f.  1.3486   1.08   0.14  0.69   18    2    81.4                              g.  1.3486.sup.(1)                                                                         1.08   0.14  0.69   18    1.27 51.6                              h.  1.1743   1.00   0.39  0.8    21    1.76 71.5                              i.  1.1743.sup.(2)                                                                         1.06   1.02  0.8    18    1.23 50                                ______________________________________                                         Remarks:                                                                      .sup.(1) acylation took place at 0-5° C.                               .sup.(2) after activation, dimethylacetamide sulfate (VI) was added to th     solution                                                                 

B) Process for the preparation of enalapril hydrochloride

To a solution of enalapril in tertiary butyl methyl ether (prepared inthe same way as in Example 1A before adding maleic acid, except forreplacing ethyl acetate with tertiary butyl methyl ether as a solvent),gaseous HCl was added. Enalapril hydrochloride began to precipitate atonce and was filtered off by suction. The salt was hygroscopic and had am.p. 35° to 40° C. (IR FIG. 7).

C) Process for the preparation of enalapril sulfate

To a solution of 96% sulfuric (VI) acid (0.07 ml) in tertiary butylmethyl ether (2 ml), a solution of enalapril (1 g) in tertiary butylmethyl ether (10 ml) (prepared as in Example 1B) was added. The sulfate,which precipitated immediately, was filtered off (quantitatively), m.p.70° to 88° C. (IR FIG. 8).

D) Process for the preparation of enalapril sodium salt

To methanol (5 ml) enalapril (0.35 g) and sodium methylate (0.05 g) wereadded. The reaction mixture was stirred for 10 minutes and then methanolwas evaporated on rotavapor. A white precipitate (yield 100%) wasisolated (IR FIG. 9).

EXAMPLE 2

It was proceeded in the same way as in the Example 1Af and after twofiltrations of imidazole hydrochloride, additional imidazole (0.693 g)was added to the system. No precipitation of imidazole hydrochloride wasobserved. After 20 hours of the reaction, enalapril maleate (1.24 g;50%) was isolated. Thus the increased concentration of imidazole reducedthe final yield.

EXAMPLE 3

It was proceeded in the same way as in Example 1Af except that only onefiltration of imidazole hydrochloride was made. The reaction time was 20hours at room temperature. The reaction mixture became dark red. Thereaction yield was 57.3% or 1.41 g.

EXAMPLE 4

Process for the preparation of enalapril maleate (using reagent (II))

Methylene chloride (22 ml) containing thionyl chloride (0.44 ml) wasdiluted to 25 ml. Imidazole (2.4769 g) was added. The reaction time andthe reaction conditions were the same as in Example 1. Imidazolehydrochloride (0.41 g) was filtered off. N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine (1.4 g) was activatedwith reagent (II) to intermediate B and the reaction with disilylatedL-proline was carried out as in Example 1. After the completed reaction,enalapril maleate (1.72 g or 41.4%) was isolated. The melting point ofenalapril maleate as measured was 144°-148° C. The melting pointmentioned in the literature is 143°-144.5° C.

EXAMPLE 5

Process for the preparation of diquinalapril sulfate

Preparation of reagent (I)

A solution (50 ml) of SOCl₂ (1 ml) in methylene chloride was prepared.The solution (22 ml) was portioned out and there were added another 3 mlof dried methylene chloride (SOCl₂ : 0.44 ml, 6.064 mmole). The reactionmixture was cooled to -15° C. and to the reaction mixture imidazole(1.348 g, 19.81 mmole) was added. The reaction was led according toTable 4. The solid precipitate was filtered off and washed with cooledmethylene chloride (5 ml). Imidazole hydrochloride (1.14 g) was dried.

                  TABLE 4                                                         ______________________________________                                        reaction time temperature                                                     (min)         (°C.)                                                                            remarks                                               ______________________________________                                         0            -15       white precipitate                                     12            -10       white precipitate                                     23             -4       white precipitate                                     40             +4       white precipitate                                     55            +17       white precipitate                                     65            +25       white precipitate                                     ______________________________________                                    

Activation of N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine

N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine (1.4 g) was added tothe slightly coloured solution of reagent (I), stirred for 45 minutes ata temperature from -15° C. to 0° C. and then for 15 minutes at atemperature from 0° C. to +15° C. and finally for 5 minutes at atemperature from +20° C. to 25° C. After the completed reaction,insoluble particles were filtered off and washed with cooled drymethylene chloride (5 ml). The precipitate (0.14 g) was isolated.

Disilylation of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid

A mixture of anhydrous methylene chloride (25 ml),1,2,3,4-tetrahydro-3-iso-quinolinecarboxylic acid hydrochloride(1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride, notsoluble in the solvent) (1.7 g) and triethylamine (2.1 ml) was taken.Trimethylsilyl chloride (1.6 ml) was added to the reaction mixture. Aslightly exothermic reaction was observed., Insoluble triethylammoniumhydrochloride precipitated from the reaction mixture. The reactionmixture was stirred at room temperature for 2 hours.

Acylation

A suspension of disilylated 1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid was added to the reaction mixture and the obtained yellowishreaction mixture was stirred for 18 hours at room temperature.

Isolation

The solvent was evaporated to dryness on rotavapor after 18 hours ofstirring and water (10 ml) saturated with sodium chloride was added.Methylene chloride (10 ml) was added to the mixture. The pH of thesolution was adjusted from 6 to 4.2 with concentrated hydrochloric acid.The aqueous phase was washed with methylene chloride (2×5 ml). Theorganic phases were combined, dried with anhydrous sodium sulfate andfiltered. A solution of tertiary butyl methyl ether (3 ml) and 96%sulfuric (VI) acid (0.1 ml) was added to the methylene chloridesolution. The solvents were evaporated on rotavapor and diquinalaprilsulfate (2.56 g) was isolated with a 92% yield and m.p. 90° C. (IR FIG.6).

EXAMPLE 6

A solution of SOCl₂ (2.2 ml) in anhydrous methylene chloride (125 ml)(treatment with 96% H₂ SO₄ and distillation) was prepared. The reactionmixture was cooled to -15° C., imidazole (6.7430 g) was added and thereaction was led according to the following Table 5.

                  TABLE 5                                                         ______________________________________                                        reaction time                                                                              temperature                                                      (min)        (°C.)                                                                            remarks                                                ______________________________________                                         0           -15       white precipitate                                      12           -10       white precipitate                                      23            -4       white precipitate                                      40            +4       white precipitate                                      55           +17       white precipitate                                      65           +20 to +25                                                                              white precipitate                                      ______________________________________                                    

The precipitate was filtered off and washed with anhydrous methylenechloride (10 ml). The solution was cooled to -15° C. and N-1-(S)-ethoxycarbonyl-3-phenyl-propyl!-L-alanine (7 g) was added. Thereaction was led according to Table 6.

                  TABLE 6                                                         ______________________________________                                        reaction time                                                                              temperature                                                      (min)        (°C.)                                                                            remarks                                                ______________________________________                                         0           -15       opalescent solution                                    15           -10       opalescent solution                                    30            -5       opalescent solution                                    45              0      opalescent solution                                    50            +5       opalescent solution                                    55           +10       opalescent solution                                    60           +15       opalescent solution                                    65           +20 to +25                                                                              opalescent solution                                    ______________________________________                                    

The insoluble particles were filtered off and washed with anhydrousmethylene chloride (10 ml). The prepared solution of silylated L-prolinewas added to the solution. The light yellow solution was stirred at roomtemperature (21° C.) for 22 hours. The solvent was evaporated to drynessat a temperature of 30°-35° C. and saturated aqueous sodium chloridesolution (50 ml H₂ O and 17 g NaCl) and ethyl acetate (25 ml) (pH 5.08)were added to the residue. It was acidified to pH 4.22 with concentratedhydrochloric acid. The aqueous phase and ester phase were separated andthe aqueous phase was washed with ethylacetate (2×15 ml), the organicphases were combined and dried with anhydrous sodium sulfate. It wasfiltered and washed with ethyl acetate (2×15 ml). Maleic acid (3 g) wasadded to the solution and enalapril maleate precipitated. The reactionmixture was stirred for another 15 minutes at room temperature, then itwas cooled to -25° C. and after 15 minutes at this temperature theprecipitate was filtered and washed with ethyl acetate (10 ml).Enalapril maleate (11.2 g; 90.73%) was obtained.

Silylation of L-proline

L-proline (3.45 g) was dissolved in anhydrous methylene chloride (125ml), trimethylamine (3.5 ml) and trimethylchlorosilane (8 ml) were added. The reaction mixture was stirred at room temperature for 90 minutes.

EXAMPLE 7

It was proceeded in the same way as in Example 6 except that silylatedL-proline was prepared in a different manner.

Silylation of L-proline

L-proline (0.69 g), triethylamine (0.9 ml) and trimethylsilylchloride(1.6 ml) were added to methylene chloride (25 ml). The reaction mixturewas stirred at room temperature for 2 hours.

Enalapril maleate (1.96 g or 79.39%) was isolated.

EXAMPLE 8

It was proceeded in the same way as in Example 6 except that silylatedL-proline was prepared in a different manner.

Silylation of L-proline

L-proline (0.69 g) and trimethylsilylchloride (1.6 ml) were added tomethylene chloride (25 ml). The reaction mixture was stirred at roomtemperature for 2 hours.

Enalapril maleate (1.32 g or 53.47%) was isolated.

EXAMPLE 9

It was proceeded in the same way as in Example 6 except that silylatedL-proline was prepared in a different manner.

Silylation of L-proline

L-proline (0.69 g), triethylamine (0.5 ml) and trimethylsilylchloride(1.6 ml) were added to methylene chloride (25 ml). The reaction mixturewas stirred at room temperature for 2 hours.

Enalapril maleate (1.81 g or 73.31%) was isolated.

The results of Examples 6 to 9 show that the best reaction yield wasachieved when such a solution of silylated L-proline entered thereaction mixture wherein disilyllated L-proline i.e.L-proline-N-trimethylsilyl-O-trimethylsilyl ester, and monosilylatedL-proline i.e. L-proline-O-trimethylsilylester hydrochloride were in a1:1 ratio.

The following Examples 10 and 11 illustrate the process whereinimidazole was replaced by benzimidazole and 2-methylimidazole in thepreparation of the reagent for activating N-1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine.

EXAMPLE 10

Preparation of activating reagent on the basis of benzimidazole

A solution (50 ml) of SOCl₂ (1 ml) in methylene chloride was prepared.The solution (22 ml) was portioned out and there were added another 3 mlof dried methylene chloride (SOCl₂ : 0.44 ml, 6.064 mmole). The reactionmixture was cooled to -15° C. and to the reaction mixture benzimidazole(2.340 g, 19.81 mmole). was added. The reaction was led according toTable 7.

                  TABLE 7                                                         ______________________________________                                        reaction time temperature                                                     (min)         (°C.)                                                                            remarks                                               ______________________________________                                         0            -15       white precipitate                                     12            -10       white precipitate                                     23             -4       white precipitate                                     40             +4       white precipitate                                     55            +17       white precipitate                                     65            +25       white precipitate                                     ______________________________________                                    

The solid precipitate was filtered and washed with cooled methylenechloride (5 ml). N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine (1.4g) was added to the solution cooled to -15° C. and it was stirred for 45minutes at a temperature from -15° C. to 0° C., then for 15 minutes at atemperature from 0° C. to +15° C. and further for 5 minutes at atemperature from +20° C. to +25° C. After the completed reactioninsoluble particles were filtered off and washed with cooled drymethylene chloride (5 ml). A suspension of disilylated L-proline wasadded to the reaction mixture and it was stirred at room temperature for18 hours.

After 18 hours of stirring, the solvent was evaporated to dryness onrotavapor and a saturated sodium chloride solution (10 ml) was added.Ethyl acetate (10 ml) was added to the mixture and the pH of thesolution was adjusted from 6 to 4.2 with concentrated hydrochlorid acid.The aqueous phase was washed with ethyl acetate (2×3 ml). The organicphases were combined, dried with anhydrous sodium sulfate and filtered.Maleic acid (0.6 g) in ethyl acetate (4 ml) was added to the ethylacetate solution. The solution was stirred at room temperature for 20minutes and then cooled to -20° C. for another 20 minutes. The obtainedprecipitate was filtered, washed with ethyl acetate and dried. Enalaprilmaleate was isolated with a good yield and a purity of >99%.

Preparation of disilylated L-proline

L-proline (0.69 g), methylene chloride (25 ml), triethylamine (0.7 ml)and trimethylsilylchloride (1.6 ml) were blended. The reaction mixturewas stirred at room temperature for 2 hours.

EXAMPLE 11

Preparation of activating agent on the basis of 2-methylimidazole

A solution (50 ml) of SOCl₂ (1 ml) in methylene chloride was prepared.The solution (22 ml) was portioned out and another 3 ml of driedmethylene chloride (SOCl₂ : 0.44 ml, 6.064 mmole) were added. Thereaction mixture was cooled to -15° C. and to the reaction mixture2-methylimidazole (1.623 g, 19.81 mmole) was added. The reaction was ledaccording to Table 8.

                  TABLE 8                                                         ______________________________________                                        reaction time temperature                                                     (min)         (°C.)                                                                            remarks                                               ______________________________________                                         0            -15       white precipitate                                     12            -10       white precipitate                                     23             -4       white precipitate                                     40             +4       white precipitate                                     55            +17       white precipitate                                     65            +25       white precipitate                                     ______________________________________                                    

The solid precipitate was filtered and washed with cooled methylenechloride (5 ml). N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine (1.4g) was added to the solution cooled to -15° C. and it was stirred for 45minutes at a temperature from -15° C. to 0° C., then for 15 minutes at atemperature from 0° C. to +15° C. and further for 5 minutes at atemperature from +20° C. to +25° C. After the completed reaction,insoluble particles were filtered off and the solid filtrate was washedwith cooled dry methylene chloride (5 ml). A suspension of disilylatedL-proline was added to the reaction mixture and it was stirred at roomtemperature for 18 hours.

After 18 hours of stirring, the solvent was evaporated to dryness onrotavapor and a saturated sodium chloride solution (10 ml) was added.Ethyl acetate (10 ml) was added to the mixture and the pH of thesolution was adjusted from 6 to 4.2 with concentrated hydrochlorid acid.The aqueous phase was washed with ethyl acetate (2×3 ml). The organicphases were combined, dried with anhydrous sodium sulfate and filtered.Maleic acid (0.6 g) in ethyl acetate (4 ml) was added to the ethylacetate solution. The solution was stirred at room temperature for 20minutes and then cooled to -20° C. for another 20 minutes. The obtainedprecipitate was filtered, washed with ethyl acetate and dried. Enalaprilmaleate was isolated with a good yield and a purity of >99%.

We claim:
 1. Process for the preparation of compounds having ACEinhibitory action of the formula ##STR20## and pharmaceuticallyacceptable salts thereof, wherein R has the following meanings ##STR21##characterized in that the carboxy group of the stereospecific amino acidN- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L-alanine of the formula##STR22## is activated with thionyl chloride derivative of the formulaI' ##STR23## or with thionyl chloride derivative of the formula II'##STR24## wherein R₁ is the residue of a heterocyclic ambident compound,in the presence of an aprotic organic solvent under elimination of theprecipitated hydrochloride of the above mentioned heterocyclic ambidentcompound, to the intermediate novel compound A ##STR25## or to theintermediate novel compound B ##STR26## and the obtained A or Bintermediate compound is reacted with an amino acid, selected from thegroup which consists of ##STR27## whereat the reaction medium must beanhydrous in all steps, and then the obtained compounds are converted topharmaceutically acceptable salts thereof in a conventional manner. 2.Process according to claim 1, characterized in that the compound offormula I' is a chlorothionylimidazole of the formula (I) ##STR28## isused.
 3. Process according to claim 1, characterized in that as thecompound of the formula II' thionyldiimidazole of the formula (II)##STR29## is used.
 4. Process according to claim 1, characterized inthat for the reaction with amino acid a mixture of monosilylated aminoacid and disilylated amino acid is used, preferably in a 1:1 ratio. 5.Process according to claim 1, characterized in that as amino acidL-proline in the form of a mixture of disilylated and monosilylatedL-proline is used.
 6. Process according to claim 1, characterized inthat disilylated L-proline, and monosilylated L-proline are in a 1:1ratio.
 7. Compound of the formula A ##STR30##
 8. Compound of the formulaB ##STR31##
 9. Process according to claim 1, characterized in that forthe reaction with amino acid a mixture of monosilylated amino acid anddisilylated amino acid is used in a 1:1 ratio.
 10. Process according toclaim 6, characterized in that said disilylated L-proline isL-proline-N-trimethylsilyl-O-trimethylsilyl ester, and saidmonosilylated L-proline is L-proline-O-trimethylsilylesterhydrochloride.
 11. Process according to claim 2, characterized in thatfor the reaction with amino acid a mixture of monosilylated amino acidand disilylated amino acid is used.
 12. Process according to claim 2,characterized in that as amino acid L-proline in the form of a mixtureof disilylated and monosilylated L-proline is used.
 13. Processaccording to claim 3, characterized in that as amino acid L-proline inthe form of a mixture of disilylated and monosilylated L-proline isused.
 14. Process according to claim 4, characterized in that as aminoacid L-proline in the form of a mixture of disilylated and monosilylatedL-proline is used.
 15. Process according to claim 14, characterized inthat said mixture is in a 1:1 ratio.
 16. Process according to claim 11,characterized in that said mixture is in a 1:1 ratio.
 17. The process ofclaim 1 wherein said heterocyclic ambident compound is selected from thegroup consisting of imidazole, benzimidazole, 2-methylimidazole andtriazole.
 18. The process of claim 17 wherein said amino acid is in amonosilylated form.
 19. The process of claim 17 wherein said amino acidis in a disilylated form.
 20. The process of claim 1 wherein said aminoacid is in a monosilylated form.
 21. The process of claim 1 wherein saidamino acid is in a disilylated form.